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1pvn

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Revision as of 07:03, 21 August 2019

The crystal structure of the complex between IMP dehydrogenase catalytic domain and a transition state analogue MZP

Structural highlights

1pvn is a 4 chain structure. This structure supersedes the now removed PDB entry 1mwf. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	1lrt
Activity:	IMP dehydrogenase, with EC number 1.1.1.205
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[IMDH_TRIFO] Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth. Could also have a single-stranded nucleic acid-binding activity and could play a role in RNA and/or DNA metabolism.^[1]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Mizoribine monophosphate (MZP) is the active metabolite of the immunosuppressive agent mizoribine and a potent inhibitor of IMP dehydrogenase (IMPDH). This enzyme catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD via a covalent intermediate at Cys319 (E-XMP). Surprisingly, mutational analysis indicates that MZP is a transition state analogue although its structure does not resemble that of the expected transition state. Here we report the X-ray crystal structure of the E.MZP complex at 2.0 A resolution that reveals a transition state-like structure and solves the mechanistic puzzle of the IMPDH reaction. The protein assumes a new conformation where a flap folds into the NAD site and MZP, Cys319, and a water molecule are arranged in a geometry resembling the transition state. The water appears to be activated by interactions with a conserved Arg418-Tyr419 dyad. Mutagenesis experiments confirm that this new closed conformation is required for the hydrolysis of E-XMP, but not for the reduction of NAD. The closed conformation provides a structural explanation for the differences in drug selectivity and catalytic efficiency of IMPDH isozymes.

The immunosuppressive agent mizoribine monophosphate forms a transition state analogue complex with inosine monophosphate dehydrogenase.,Gan L, Seyedsayamdost MR, Shuto S, Matsuda A, Petsko GA, Hedstrom L Biochemistry. 2003 Feb 4;42(4):857-63. PMID:12549902^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Digits JA, Hedstrom L. Kinetic mechanism of Tritrichomonas foetus inosine 5'-monophosphate dehydrogenase. Biochemistry. 1999 Feb 23;38(8):2295-306. PMID:10029522 doi:http://dx.doi.org/10.1021/bi982305k
↑ Gan L, Seyedsayamdost MR, Shuto S, Matsuda A, Petsko GA, Hedstrom L. The immunosuppressive agent mizoribine monophosphate forms a transition state analogue complex with inosine monophosphate dehydrogenase. Biochemistry. 2003 Feb 4;42(4):857-63. PMID:12549902 doi:10.1021/bi0271401

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1pvn"

@@ Line 1: / Line 1: @@
 ==The crystal structure of the complex between IMP dehydrogenase catalytic domain and a transition state analogue MZP==
-<StructureSection load='1pvn' size='340' side='right' caption='[[1pvn]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+<StructureSection load='1pvn' size='340' side='right'caption='[[1pvn]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[1pvn]] is a 4 chain structure. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=1mwf 1mwf]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PVN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1PVN FirstGlance]. <br>
@@ Line 15: / Line 15: @@
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/pv/1pvn_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/pv/1pvn_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
@@ Line 30: / Line 30: @@
 </div>
 <div class="pdbe-citations 1pvn" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Inosine monophosphate dehydrogenase|Inosine monophosphate dehydrogenase]]
 == References ==
 <references/>
@@ Line 35: / Line 38: @@
 </StructureSection>
 [[Category: IMP dehydrogenase]]
+[[Category: Large Structures]]
 [[Category: Gan, L]]
 [[Category: Hedstrom, L]]

1pvn

From Proteopedia

Revision as of 07:03, 21 August 2019

The crystal structure of the complex between IMP dehydrogenase catalytic domain and a transition state analogue MZP

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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